Castration-Resistant Prostate Cancer (CRPC) is a leading cause of cancer-related death in men. Despite progress in systemic therapy for CRPC, improvements in survival are modest, and virtually all patients succumb to this disease within about 2 years. The primary cause of morbidity and mortality in CRPC is metastasis to the bone, which occurs in about 90% of cases.
Metastasis to the bone is a complex process that involves interactions between cancer cells and components of the bone microenvironment including osteoblasts, osteoclasts, and endothelial cells. Bone metastases cause local disruption of normal bone remodeling, and lesions generally show a propensity for either osteoblastic (bone-forming) or osteolytic (bone-resorbing) activity. Although most CRPC patients with bone metastases display features of both types of lesions, prostate cancer bone metastases are often osteoblastic, with abnormal deposition of unstructured bone accompanied by increased skeletal fractures, spinal cord compression, and severe bone pain.
The receptor tyrosine kinase MET plays important roles in cell motility, proliferation, and survival, and it has been shown to be a key factor in tumor angiogenesis, invasiveness, and metastasis. Prominent expression of MET has been observed in primary and metastatic prostate carcinomas, with evidence for higher levels of expression in bone metastases compared to lymph node metastases or primary tumors.
Vascular endothelial growth factor (VEGF) and its receptors on endothelial cells are widely accepted as key mediators in the process of tumor angiogenesis. In prostate cancer, elevated VEGF in either plasma or urine is associated with shorter overall survival. VEGF may also play a role in activating the MET pathway in tumor cells by binding to neuropilin-1, which is frequently unregulated in prostate cancer and appears to activate MET in a co-receptor complex. Agents targeting the VEGF signaling pathway have demonstrated some activity in patients with CRPC.
MET signalling can influence osteoblast and osteoclast function. Strong immunohistochemical staining of MET has been observed in osteoblasts in developing bone, while both HGF and MET are expressed by osteoblasts and osteoclasts in vitro and regulate cellular responses such as proliferation, migration and differentiation. Secretion of HGF by osteoblasts has been proposed as a key factor in osteoblast/osteoclast coupling [58] and is thought to promote the development of bone metastases by tumour cells that express MET.
Like MET, the VEGF signalling pathway is strongly implicated in bone formation and remodelling. Both osteoblasts and osteoclasts express VEGF and VEGF receptors, which appear to be involved in autocrine and/or paracrine feedback mechanisms regulating cell proliferation, migration, differentiation and survival. Experiments using genetically modified mice have shown that angiogenesis and VEGF signalling in osteoblasts are both important in bone development and repair.
Thus, a need remains for methods of treating prostate cancer, including CRPC and the associated osteolytic bone metastases.